Faculty Bibliography

Phase-contrast (PC) cine MRI is a promising method for assessment of pathologic hemodynamics, including cardiovascular and hepatoportal vascular dynamics, but its low data acquisition efficiency limits the achievable spatial and temporal resolutions within clinically acceptable breath-hold durations. We propose to accelerate PC cine MRI using an approach which combines compressed sensing and parallel imaging (k-t SPARSE-SENSE). We validated the proposed 6-fold accelerated PC cine MRI against 3-fold accelerated PC cine MRI with parallel imaging (generalized autocalibrating partially parallel acquisitions). With the programmable flow pump, we simulated a time varying waveform emulating hepatic blood flow. Normalized root mean square error between two sets of velocity measurements was 2.59%. In multiple blood vessels of 12 control subjects, two sets of mean velocity measurements were in good agreement (mean difference = -0.29 cm/s; lower and upper 95% limits of agreement = -5.26 and 4.67 cm/s, respectively). The mean phase noise, defined as the standard deviation of the phase in a homogeneous stationary region, was significantly lower for k-t SPARSE-SENSE than for generalized autocalibrating partially parallel acquisitions (0.05 +/- 0.01 vs. 0.19 +/- 0.06 radians, respectively; P < 0.01). The proposed 6-fold accelerated PC cine MRI pulse sequence with k-t SPARSE-SENSE is a promising investigational method for rapid velocity measurement with relatively high spatial (1.7 mm x 1.7 mm) and temporal ( approximately 35 ms) resolutions. Magn Reson Med, 2011. (c) 2011 Wiley Periodicals, Inc.

Genetics plays an important role in establishing susceptibility to nephrolithiasis, although diet and other environmental factors make major contributions. In a small number of patients, the genetic causes of stones are more clearly established. Four of these hereditary diseases include primary hyperoxaluria, Dent disease, cystinuria, and adenine phosphoribosyltransferase deficiency, which results in 2,8-dihydroxyadenine stones. Patients with these disorders often experience recurring stones from early childhood, requiring frequent hospitalizations and procedures. They are at risk of kidney damage and chronic kidney disease. Because of their rarity, these four disorders are difficult to study and recognize. This in turn slows progress toward effective therapies and increases the risk of misdiagnosis or diagnosis late in the course of the disease. Therefore, patients may experience unnecessary and harmful treatments and accelerated loss of kidney function. In this article, we will review the pathogenesis, clinical presentation, diagnosis of and treatments for these four disorders. 2011 Springer Science+Business Media, LLC

Greater intra-subject variability (ISV) in response time is a heritable endophenotype of attention-deficit/hyperactivity disorder (ADHD). Spontaneous low frequency oscillations (LFO: 0.01-0.1 Hz) observed in brain functional magnetic resonance signals might account for such behavioral variability. Recently, we demonstrated that ISV in response time (RT) explained ratings of ADHD symptoms. Building on this finding, here we hypothesized that LFO in RT time series would explain these ratings, both independently and in addition to RT coefficient of variation (CV). To measure RT LFO, we applied Morlet wavelet transform to the previously collected RT data. Our community sample consisted of 98 children (including 66 boys, mean age 9.9 +/- 1.4 years), who completed four computer Tasks of Executive Control. Conners' Parent Rating Scale ratings were obtained. RT LFO of three tasks significantly explained ratings of inattention, hyperactivity and three global Conners' subscales. In addition, RT LFO during two tasks that included an inhibitory component increased the proportions of variance explained in subscales of both inattention and hyperactivity/impulsivity, beyond the effects of RT-CV. Three specific low frequency bands (Slow-5: 0.01-0.027 Hz; Slow-4: 0.027-0.073 Hz; Slow-3: 0.073-0.20 Hz) were strongly related to the ADHD scales. We conclude that RT LFO predict dimensional ratings of ADHD symptoms both independently and in addition to RTCV. Results suggest that frequency analyses are a suitable methodology to link behavioral responses to putative underlying physiological processes.

The effective delivery of a therapeutic drug to the core of a tumor is often impeded by physiological barriers, such as the interstitial fluid pressure (IFP). There are a number of therapies that can decrease IFP and induce tumor vascular normalization. However, a lack of a noninvasive means to measure IFP hinders the utilization of such a window of opportunity for the maximization of the treatment response. Thus, the purpose of this study was to investigate the feasibility of using intravoxel incoherent motion (IVIM) diffusion parameters as noninvasive imaging biomarkers for IFP. Mice bearing the 4T1 mammary carcinoma model were studied using diffusion-weighted imaging (DWI), immediately followed by wick-in-needle IFP measurement. Voxelwise analysis was conducted with a conventional monoexponential diffusion model, as well as a biexponential model taking IVIM into account. There was no significant correlation of IFP with either the median apparent diffusion coefficient from the monoexponential model (r = 0.11, p = 0.78) or the median tissue diffusivity from the biexponential model (r = 0.30, p = 0.44). However, IFP was correlated with the median pseudo-diffusivity (D(p) ) of apparent vascular voxels (r = 0.76, p = 0.02) and with the median product of the perfusion fraction and pseudo-diffusivity (f(p) D(p) ) of apparent vascular voxels (r = 0.77, p = 0.02). Although the effect of IVIM in tumors has been reported previously, to our knowledge, this study represents the first direct comparison of IVIM metrics with IFP, with the results supporting the feasibility of the use of IVIM DWI metrics as noninvasive biomarkers for tumor IFP

Thyroid hormone is critical for central nervous system development. Fetal hypothyroidism leads to reduced cognitive performance in offspring as well as other effects on neural development in both humans and experimental animals. The nature of these impairments suggests that thyroid hormone may exert its effects via dysregulation of the neurotrophin brain-derived neurotrophic factor (BDNF), which is critical to normal development of the central nervous system and has been implicated in neurodevelopmental disorders. The only evidence of BDNF dysregulation in early development, however, comes from experimental models in which severe prenatal hypothyroidism occurred. By contrast, milder prenatal hypothyroidism has been shown to alter BDNF levels and BDNF-dependent functions only much later in life. We hypothesized that mild experimental prenatal hypothyroidism might lead to dysregulation of BDNF in the early postnatal period. BDNF levels were measured by ELISA at 3 or 7 d after birth in different regions of the brains of rats exposed to propylthiouracil (PTU) in the drinking water. The dose of PTU that was used induced mild maternal thyroid hormone insufficiency. Pups, but not the parents, exhibited alterations in tissue BDNF levels. Hippocampal BDNF levels were reduced at both d 3 and 7, but no significant reductions were observed in either the cerebellum or brain stem. Unexpectedly, more males than females were born to PTU-treated dams, suggesting an effect of PTU on sex determination. These results support the hypothesis that reduced hippocampal BDNF levels during early development may contribute to the adverse neurodevelopmental effects of mild thyroid hormone insufficiency during pregnancy.

Since ion channels move electrical charge during their activity, they have traditionally been studied using electrophysiological approaches. This was sometimes combined with mathematical models, for example with the description of the ionic mechanisms underlying the initiation and propagation of action potentials in the squid giant axon by Hodgkin and Huxley. The methods for studying ion channels also have strong roots in protein chemistry (limited proteolysis, the use of antibodies, etc.). The advent of the molecular cloning and the identification of genes coding for specific ion channel subunits in the late 1980s introduced a multitude of new techniques with which to study ion channels and the field has been rapidly expanding ever since (e.g. antibody development against specific peptide sequences, mutagenesis, the use of gene targeting in animal models, determination of their protein structures) and new methods are still in development. This review focuses on techniques commonly employed to examine ion channel function in an electrophysiological laboratory. The focus is on the K(ATP) channel, but many of the techniques described are also used to study other ion channels.

Fetal alcohol exposure can cause developmental defects in offspring known as fetal alcohol spectrum disorder (FASD). FASD symptoms range from obvious facial deformities to changes in neuroanatomy and neurophysiology that disrupt normal brain function and behavior. Ethanol exposure at postnatal day 7 in C57BL/6 mice induces neuronal cell death and long-lasting neurobehavioral dysfunction. Previous work has demonstrated that early ethanol exposure impairs spatial memory task performance into adulthood and perturbs local and interregional brain circuit integrity in the olfacto-hippocampal pathway. Here we pursue these findings to examine whether lithium prevents anatomical, neurophysiological, and behavioral pathologies that result from early ethanol exposure. Lithium has neuroprotective properties that have been shown to prevent ethanol-induced apoptosis. Here we show that mice co-treated with lithium on the same day as ethanol exposure exhibit dramatically reduced acute neurodegeneration in the hippocampus and retain hippocampal-dependent spatial memory as adults. Lithium co-treatment also blocked ethanol-induced disruption in synaptic plasticity in slice recordings of hippocampal CA1 in the adult mouse brain. Moreover, long-lasting dysfunctions caused by ethanol in olfacto-hippocampal networks, including sensory-evoked oscillations and resting state coherence, were prevented in mice co-treated with lithium. Together, these results provide behavioral and physiological evidence that lithium is capable of preventing or reducing immediate and long-term deleterious consequences of early ethanol exposure on brain function.

Herpes simplex virus type-1 (HSV-1) establishes latency in peripheral neurons, creating a permanent source of recurrent infections. The latent genome is assembled into chromatin and lytic cycle genes are silenced. Processes that orchestrate reentry into productive replication (reactivation) remain poorly understood. We have used latently infected cultures of primary superior cervical ganglion (SCG) sympathetic neurons to profile viral gene expression following a defined reactivation stimulus. Lytic genes are transcribed in two distinct phases, differing in their reliance on protein synthesis, viral DNA replication and the essential initiator protein VP16. The first phase does not require viral proteins and has the appearance of a transient, widespread de-repression of the previously silent lytic genes. This allows synthesis of viral regulatory proteins including VP16, which accumulate in the cytoplasm of the host neuron. During the second phase, VP16 and its cellular cofactor HCF-1, which is also predominantly cytoplasmic, concentrate in the nucleus where they assemble an activator complex on viral promoters. The transactivation function supplied by VP16 promotes increased viral lytic gene transcription leading to the onset of genome amplification and the production of infectious viral particles. Thus regulated localization of de novo synthesized VP16 is likely to be a critical determinant of HSV-1 reactivation in sympathetic neurons.

Electrophysiological recordings from behaving animals provide an unparalleled view into the functional role of individual neurons. Intracellular approaches can be especially revealing as they provide information about a neuron's inputs and intrinsic cellular properties, which together determine its spiking output. Recent technical developments have made intracellular recording possible during an ever-increasing range of behaviors in both head-fixed and freely moving animals. These recordings have yielded fundamental insights into the cellular and circuit mechanisms underlying neural activity during natural behaviors in such areas as sensory perception, motor sequence generation, and spatial navigation, forging a direct link between cellular and systems neuroscience.